Cancer is one of the most significant diseases confronting mankind, and much research effort is going into the treatment thereof. In cancer treatment, particularly in the medical therapy of cancer, various anticancer agents for suppressing the growth of cancer cells have been developed, and some degree of success has been achieved, but since such drugs suppress the growth of not only cancer cells but also normal cells, there are problems with various side effects such as nausea and vomiting, hair loss, myelosuppression, kidney damage, and nerve damage. As an approach to reduce such side effects, attempts have been made in recent years to specifically deliver an anticancer agent to cancer cells or cancer tissue. By specific delivery of an anticancer agent, is it is not only possible to prevent the anticancer agent from reaching normal cells and reduce the side effects, but also to obtain the economic benefit that the dose of the anticancer agent can be decreased.
As a concrete example of a delivery method, there have been developed techniques such as passive targeting in which the EPR (enhanced permeability and retention) effect is utilized and active targeting in which a drug is modified by a ligand for a surface molecule that is specifically expressed on cancer cells. As molecules that can be utilized in active targeting, molecules that are endocytosed into cells as a result of ligand bonding, such as, for example, CD19, HER2, a transferrin receptor, a folate receptor, a VIP receptor, EGFR (Nonpatent Publication 1), RAAG10 (Patent Publication 1), PIPA (Patent Publication 2), and KID3 (Patent Publication 3) have been reported. However, none of the delivery methods are yet satisfactory, and there has been a further desire for the development of cancer cell-specific delivery methods.
Furthermore, in the medical therapy of cancer, from the idea that a cancer can be cured by killing the cancer cells themselves, various anticancer agents targeted at cancer cells have been developed and used. However, such attempts could not always achieve satisfactory results because of the above-mentioned problems with side effects, or the occurrence of additional phenomena such as relapse due to minimal residual disease, resistance of tumor cells to the anticancer agent, etc.
On the other hand, as a result of recent research, it has gradually become clear that the environment around a cancer, for example, interstitial tissue which includes blood vessels, ECM, and fibroblasts, plays an important role in the onset and progression of the cancer. For example, Camps et al. (see Nonpatent Publication 2) reported that when an athymic nude mouse was inoculated with tumor cells that do not form a tumor on their own or for which the tumor formation rate is low, together with tumorigenic fibroblasts, rapid and marked formation of a tumor was observed, and Olumi et al. (see Nonpatent Publication 3) reported that when peritumoral fibroblasts (i.e. CAFs) from a prostate tumor patient were grafted on an athymic animal together with human prostate cells, the neoplastic growth thereof was markedly accelerated. Furthermore, it has been clarified that a bioactive substance such as PDGF (platelet-derived growth factor), TGF-β (transforming growth factor-β), HGF (hepatocyte growth factor), or SDF-1 (stromal cell-derived factor-1) produced in the interstitium is involved in such growth of a tumor (see Nonpatent Publication 4).
From these findings, the importance of the environment around a cancer has been brought to the fore, and new treatment methods that, rather than the cancer cells themselves, are targeted at the environment around them have been investigated. Among them, CAFs, which secrete various bioactive substances and are deeply involved in the onset and progression of cancer, have been attracting attention in recent years, but fundamental research thereinto only has a short history of 10 or so years, and although some of the cancer treatment methods that are targeted at bioactive substances secreted from CAFs have been recognized as having some degree of effect, in the current situation none is recognized as having any effect as a cancer treatment method targeted at CAFs themselves (see Nonpatent Publication 4).